title: RIP3 mediates the embryonic lethality of caspase-8-deficient mice.
abstract: Apoptosis and necroptosis are complementary pathways controlled by common signalling adaptors, kinases and proteases; among these, caspase-8 (Casp8) is critical for death receptor-induced apoptosis. This caspase has also been implicated in non-apoptotic pathways that regulate Fas-associated via death domain (FADD)-dependent signalling and other less defined biological processes as diverse as innate immune signalling and myeloid or lymphoid differentiation patterns. Casp8 suppresses RIP3-RIP1 (also known as RIPK3-RIPK1) kinase complex-dependent necroptosis that follows death receptor activation as well as a RIP3-dependent, RIP1-independent necrotic pathway that has emerged as a host defence mechanism against murine cytomegalovirus. Disruption of Casp8 expression leads to embryonic lethality in mice between embryonic days 10.5 and 11.5 (ref. 7). Thus, Casp8 may naturally hold alternative RIP3-dependent death pathways in check in addition to promoting apoptosis. We find that RIP3 is responsible for the mid-gestational death of Casp8-deficient embryos. Remarkably, Casp8(-/-)Rip3(-/-) double mutant mice are viable and mature into fertile adults with a full immune complement of myeloid and lymphoid cell types. These mice seem immunocompetent but develop lymphadenopathy by four months of age marked by accumulation of abnormal T cells in the periphery, a phenotype reminiscent of mice with Fas-deficiency (lpr/lpr; also known as Fas). Thus, Casp8 contributes to homeostatic control in the adult immune system; however, RIP3 and Casp8 are together completely dispensable for mammalian development.
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA. wkaiser@emory.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.forename: Jason W
authors.initials: JW
authors.lastname: Upton
authors.forename: Alyssa B
authors.initials: AB
authors.lastname: Long
authors.forename: Devon
authors.initials: D
authors.lastname: Livingston-Rosanoff
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Daley-Bauer
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Tamara
authors.initials: T
authors.lastname: Caspary
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism*; D061945:Caspase Inhibitors; D002460:Cell Line; D020964:Embryo Loss / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D017353:Gene Deletion; D007121:Immunocompetence / Q000235:genetics / Q000276:immunology; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D061945:Caspase Inhibitors; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8